Synthesis and biological properties of a series of optically active 2-oxaisocephems

A novel series of (6 S, 7 S)-3,7-disubstituted-8-oxo-1-aza-4-oxabicyclo[4.2.0]oct-2-ene-2-carboxylic acids 9a-o, parenteral optically active 2-oxaisocephems, was synthesized, and in vitro and in vivo activities were determined against Gram-positive and Gram-negative bacteria. The 7-[2-(2-aminothiazol-4-yl)-2-(Z)-cyclopentyloxyimino]acetamido derivatives, 9g, 9m and 9o, had enhanced antibacterial activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis while maintaining Gram-negative activity. It is also significant that these compounds showed more potent activity against MRSA and E. faecalis isolates than cefuzonam (10) and flomoxef (12), which are the most popular third-generation antibiotics. The combination of the 7-[2-(aminothiazol-4-yl)-2-(Z)-cyclopentyloxyimino]acetamido group and 2-oxaisocephem nucleus contributes to the increased antibacterial activity against these clinical isolates. The 7-[2-(2-aminothiazol-4-yl)-2-(Z)-cyclopentyloxyimino]acetamido derivative 9g provided good subcutaneous efficacy and exhibited more potent activity than cefmenoxime (11) against the systemic infection with S. aureus Smith in mice. The compound 9a with a [2-(2-aminothiazol-4-yl)-2-(Z)-methoxyimino]acetamido group at the 7-position showed high in vivo efficacy on the experimental infection caused by Escherichia coli No. 29 in mice. The synthesis and vitro and vivo antibacterial activities of optically active 2-oxaisocephems of novel types of antibiotics are described.